The piperazinyl butyrophenone compound with which the present inventive method is concerned has been referred to in the prior art as BMY 14802 and also MJ 14802. The synthesis of the compound and a disclosure of its antipsychotic properties are described by Yevich, et al., in U.S. Pat. No. 4,605,655. ##STR1##
Brain cells are particularly vulnerable to damage caused by ischemic conditions. Brain ischemia, or insufficient oxygen, may result from injury or disease and may last from only transient periods of time to periods of lengthy duration, as in stroke or following cardiac arrest. The principle disease associated with brain ischemia is ischemic cerebral vascular disease (ICVD), and in general refers to the disorders resulting from an insufficient supply of blood, with its nourishing oxygen content, to brain areas.
Seizures and stroke are two frequent manifestations of ischemic cerebral vascular disease. There can be many underlying causes of cerebral vascular ischemia, with several of the more common listed below;
Atherosclerosis--the most common underlying condition and may be caused either by hemodynamic or thromboembolic mechanisms. PA1 Hypertension--can impair cardiac function and/or alter cerebral circulation. PA1 Cardiac disease--comprises such disorders as cardiac arrhythmias, congestive heart failure, myocardial infarction, and the like. PA1 Hematologic disorders--increased viscosity of blood or other deleterious blood alterations. PA1 Arteritis--inflammation of intracranial arteries, may be of either infective or noninfective origin. PA1 Head injury--injuries compromising cerebral blood supply or altering the cerebral circulation. PA1 Vasospasm--decreased blood flow due to constrictive spasms of the vasculature.
As a result of ischemia in the cerebral vasculature, various clinical disorders may result. These disorders may range from transient ischemic attacks to a permanently disabling stroke. Transient ischemic attacks (TIAs) are brief (usually less than one hour) spells characterized by symptoms referable to vascular territories in the retinal, carotid, or vertibrobasilar circulation. These spells indicate a high risk for subsequent stroke, a serious disorder of more lengthy duration. Stroke, also called "cerebral vascular accident" or "cerebral crisis" refers to a sudden apoplectic attack ordinarily due to cerebral infarction, hemorrhage, or vasospasm and usually characterized by some degree of paralysis. The immediate 72 hours following stroke onset is a critical time interval since the degree of brain damage suffered may be reversible to some extent if the anoxic conditions can be eased. When the brain is deprived of oxygen, due to stroke, heart attack, or other cause; nerve damage can become irreversible and virtually untreatable. It is one object of this invention to prevent the nerve cell damage caused by ischemia. Current methods for treating stroke and brain ischemia necessarily focus on preventing hypoxia and restoring adequate blood circulation. There are no accepted methods for protecting brain cells subjected to ischemic conditions.
Various therapies have been employed in efforts to treat acute strokes and prevent significant persisting neurological deficients. Types of agents employed have been vasodilators, such as papaverine, prostacyclin, and pentoxifylline; hemodilution agents, thrombolytic agents such as tissue plasminogen activator (TPA) and calcium channel blockers; and anticoagulants such as heparin or warfarin. Transient ischemic attacks are generally treated with either anticoagulants or antiaggregators such as aspirin.
There are, at present, no effective, approved treatments which may be used therapeutically and/or prophylactically to minimize the brain cell damage caused by ischemic conditions. It is an objective of this invention to provide such a treatment that will protect brain cells from ischemia-induced damage.
Several compounds have been disclosed as being under study as potential protective agents for anoxic brain cells.
An experimental drug, MK-801, is being studied to determine its effectiveness in limiting neuronal injury after ischemia (Barnes, Science, VOL. 235, pp 632-633, Feb. 6, 1987). ##STR2##
Dextromethorphan, the non-narcotic cough suppressant, and ketamine have also been disclosed as being effective in protecting brain cells under anoxic conditions by Simon in "Frontiers in Excitatory Amino Acid Research", pages 639-644, .COPYRGT. 1988 Alan R. Liss, Inc.
Gotti, et al., JPET. 247/3, pages 1211-1221 (1988); have disclosed that ifenprodil and a derivative are effective in tissue sparing in animal models of stroke and brain infarction. ##STR3##
Wauquier, et al., in "Drug Development Research", 8/373-380 (1986) disclosed that Sabeluzole (R 58,735) is a potent antihypoxic agent with anticonvulsant properties. ##STR4##
A series of anti-anoxic 2-[4-benzoyl-1-piperidinyl)-1-phenylalkanol derivatives, having some structural resemblance to ifenprodil type compounds, is disclosed in U.S. Pat. No. 4,711,899 issued in December, 1987 to Gaudilliere, et al.
There is nothing in these references, or in the general prior art, to suggest the method of the present invention--that administration of BMY 14802 would effectively protect brain cells against ischemia.